Metabolic diseases are a group of conditions characterized by an alteration or disturbance in metabolic function. Metabolic diseases include, but are not limited to, obesity, hyperglycemia, prediabetes, diabetes (Type 1 and Type 2), insulin resistance, and metabolic syndrome.
Obesity is defined as the accumulation of excess adipose tissue resulting from various metabolic disorders. Obesity and the related metabolic syndrome have become a worldwide epidemic . Metabolic syndrome refers to a clustering of established and emerging cardiovascular disease (CVD) risk factors within a single individual. The established risk factors are obesity, diabetes, dyslipidemia, and hypertension. The symptoms of this syndrome include high blood pressure, high triglycerides, and decreased HDL. Insulin resistance is also an important factor in this syndrome's etiology.
Type 2 diabetes mellitus (T2DM) is a disease that is exacerbated by over nutrition. The onset and progression of T2DM is associated with excess fat accumulation in the abdomen, muscles, and liver. Resistance to the biological effects of insulin, a peptide hormone, represents one of the hallmarks of the development of type 2 diabetes. There is a direct effect of impaired insulin action on the dysregulation of glucose and lipid homeostasis, and insulin resistance predisposes to obesity, atherosclerosis, and cardiovascular diseases. Diabetes and obesity are therefore closely interlinked and are often referred collectively as diabesity.
Nuclear receptors (NRs) comprise a superfamily of ligand-regulated, DNA-binding transcription factors, which can both activate and repress gene expression. Nuclear receptors play an important role in metabolism. The peroxisome proliferator-activated receptors (PPARs) are the master regulators of adipogenesis and insulin action. The thyroid hormone receptors (TRs) mediate cholesterol and triglyceride metabolism. The liver X receptors (LXRs) are critical for whole body cholesterol homeostasis and are counteracted by the farnesoid X receptors (FXRs) in terms of controlling cholesterol and triglyceride metabolism and clearance. All these nuclear receptors use overlapping coregulators to modulate gene transcription.
SMRT is a major corepressor of nuclear receptors and can regulate a broad range of their functions. SMRT mediates transcriptional activity of a wide variety of transcriptional factors including regulators involved in thyroid hormone and retinoic acid signaling. Corepressors, including SMRT, are generally considered undruggable. Small molecules previously designed to target SMRT lack specificity resulting in undesirable side affects.